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. 2025 Mar 11;20(3):e0318689.
doi: 10.1371/journal.pone.0318689. eCollection 2025.

Genetic subtyping by Whole Exome Sequencing across Diffuse Large B Cell Lymphoma and Plasmablastic Lymphoma

Aitana Avendaño Pomares  1 , Laura Rodríguez Merino  1 , Sonia González  2 , Jordi Morata  3 , Raúl Tonda  3 , Patricia Arribas  1 , José Revert  1 , Estrella Carrillo  4 , Carlos Grande  5 , Josep Maria Roncero  6 , Jaime Pérez de Oteyza  7 , Concepción Nicolás  8 , Norma Gutierrez  9 , Pau Abrisqueta  10 , Antonio Gutiérrez  11 , Ángel Ramírez-Páyer  8 , Alejandro Martin Garcia-Sancho  9 , Eva González-Barca  12 , Santiago Montes-Moreno  1 ; GELTAMO group (Grupo Español de Linfomas y Trasplante Autólogo de Medula Osea), Spain
Affiliations

Genetic subtyping by Whole Exome Sequencing across Diffuse Large B Cell Lymphoma and Plasmablastic Lymphoma

Aitana Avendaño Pomares et al. PLoS One. .

Abstract

Diffuse Large B-Cell Lymphoma (DLBCL) is a heterogeneous disease characterized by a limited number of molecularly defined subtypes. Recently, genomic-based algorithms have been proposed for the classification of this disease. The whole exome sequencing was conducted on 108 diagnostic samples of diffuse large B-cell lymphoma (DLBCL). Somatic variants, predicted copy number alterations (CNAs), and available fusion data were utilized to classify the cases. Additionally, the enrichment of mutations in the TP53, MYC, and MAPK/ERK pathways was analyzed. Genetic subtypes were identified in approximately 55% of the cases. Cases with a specific genetic subtype exhibited a significantly higher Tumor Mutation Burden compared to molecularly unclassified cases (Mann-Whitney U test, p = 0.024). The prevalence of subtypes varied according to the cell of origin phenotypes. GC-B type DLBCL NOS were classified as EZB (5 cases, 16%), ST2 (5 cases, 16%), and BN2 (1 case, 3%). Four cases (13%) were genetically composite. Three cases of HGBCL/DLBCL double-hit (MYC & BCL2) were classified as EZB-MYC. Forty-three non-GC-B type DLBCL cases were classified as ST2 (5 cases, 11%), BN2 (6 cases, 14%), and MCD (3 cases, 7%). Nine cases were genetically composite (20%). MYC pathway mutations were enriched in cases with EZB and ST2 genetic features, while they were absent in the MCD subtype. TP53 mutations were identified in 11% of the cases. Plasmablastic lymphomas exhibit genetic diversity, with 27% of tumors classified as ST2. Recurrent somatic mutations indicate dysregulation of the JAK/STAT, MAPK/ERK, and tyrosine kinase signaling pathways.

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Conflict of interest statement

The authors have the following competing interests to declare: Jaime Perez de Oteyza Speakers bureau: Roche, Incyte, Servier Research funding: Pharmacyclics Angel Ramirez Payer Honoraria: Janssen, BMS, Novartis, Roche, EUSA Pharma, Abbvie, Astra Zeneca, Sanofi, Takeda, Incyte, GSK Consulting/Advisory: Janssen, BMS, Pfizer, Roche, Abbvie, Gilead, Novartis, Takeda; Astra Zeneca, Beigene Eva Gonzalez Barca Consultancy: Johnson & Johnson , Abbvie, Kiowa, Beigene, SOBI, Astra-Zeneca Speaker: Johnson & Johnson, Abbvie, Takeda, Astra-Zeneca, Lilly Travel: Johnson & Johnson, Abbvie, AstraZeneca Sonia Gonzalez Speaker´s Honoraria: Roche, Janssen, EusaPharma, Beigene, Takeda, Incyte, KITE-Pharma Advisory Board: Incyte, SOBI, Roche, Abbvie,Astrazeneca Travel/acommodation: Kite-Pharma, Roche Alejandro Martin Garcia-Sancho Honoraria and or consulting fees: Abbvie, AstraZeneca, BeiGene, BMS, Genmab, Gilead / Kite, GSK, Ideogen, Incyte, Janssen, Kyowa Kirin, Lilly, Miltenyi, Regeneron, Roche, Sobi, Takeda Research support: Gilead / Kite Santiago Montes-Moreno Speaker´s Honoraria: Roche, Janssen, Recordati Rare Diseases There are no patents, products in development or marketed products associated with this research to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The rest of co-authors do not declare any potential conflict of interest related to this paper.

Figures

Fig 1
Fig 1. Genetic Classification by Lymphgen. A.
Genetic classification by Lymphgen identified a specific subgroup in fifty-three cases (49%), while the remaining fifty-five cases were classified as unclassified (molecular subtype NOS/Other). B. DLBCL cases exhibited a similar distribution of genetic subtypes, with ST2 being the most prevalent subtype. C. A Sankey plot illustrating the genetic subtyping by Lymphgen across various large B-cell lymphoma entities. Notably, some entities, such as HGBCL/DLBCL DH, display homogeneous genetic features (i.e., EZB subtype). D. A Sankey plot depicting the genetic subtyping by Lymphgen according to cell of origin subtypes in DLBCL NOS cases. As shown, EZB is preferentially associated with GCB-type DLBCL, while both MCD and BN2 subtypes demonstrate a higher prevalence in non-GCB-type DLBCL tumors.
Fig 2
Fig 2. Analysis of MYC target pathways in DLBCL cases based on genetic subtype.
MYC gene targets exhibited significant mutations in cases with specific genetic subtypes, in contrast to molecular NOS cases (Chi-square p <  0.001). Notably, there were no MYC target mutations observed in cases classified as pure MCD genetic subtype. B. Analysis of the TP53 pathway in DLBCL cases according to genetic subtype. TP53 heterozygous deletions were identified through predicted copy number alterations (CNAs) in seven out of 86 DLBCL cases (1 A53, 2 ST2, and 4 molecular NOS/Other). Somatic mutations in the TP53 pathway (including mutations in ATM, TP53, RPS6KA3, MDM4, CHECK2, and MDM2) were detected in 23 out of 46 (50%) genetically classified cases and in 9 out of 40 (22%) cases from the molecular NOS group. Somatic mutations in the TP53 pathway were significantly enriched in cases with defined genetic subtypes (Chi-square, p <  0.001). Reason: Improved clarity, readability, and technical accuracy while maintaining the original meaning.
Fig 3
Fig 3
A. Prevalence of the ST2 genetic subtype in cases of plasmablastic lymphoma. B. Detailed analysis of LymphGen genetic features, highlighting an enrichment of genes associated with the ST2 subtype. C. Overview of protein localization for recurrent somatic mutations in TET2, TRRAP, PRRC2C, PABPC1, and STAT3.
Fig 4
Fig 4
A. Enrichment of the RTK-RAS pathway in plasmablastic lymphoma. Note the recurrent mutations in the MAPK/ERK pathway, including NF1, BRAF, NRAS, KRAS, MAPK3, as well as NTRK2, NTRK3, and ROS1. B1. Analysis of TP53 target pathways in plasmablastic lymphoma cases according to genetic subtype. Structural aberrations of TP53 (heterozygous/homozygous loss) were absent in the twenty-two plasmablastic lymphoma cases. The TP53 pathway was significantly mutated in cases with ST2 genetics. B2. Analysis of MYC target pathways in plasmablastic lymphoma cases based on genetic subtype. MYC targets were recurrently mutated in this entity, particularly in cases with the ST2 and ST2/EZB genetic subtypes (4 out of 6 cases, 66%), regardless of the presence of MYC translocation as determined by FISH.
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References

    1. Alaggio R, Amador C, Anagnostopoulos I, Attygalle AD, Araujo IB de O, Berti E, et al.. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms. Leukemia. 2022;36(7):1720–48. doi: 10.1038/s41375-022-01620-2 - DOI - PMC - PubMed
    1. Schmitz R, Wright GW, Huang DW, Johnson CA, Phelan JD, Wang JQ, et al.. Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma. N Engl J Med. 2018;378(15):1396–407. doi: 10.1056/NEJMoa1801445 - DOI - PMC - PubMed
    1. Chapuy B, Stewart C, Dunford AJ, Kim J, Kamburov A, Redd RA, et al.. Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes. Nat Med. 2018;24(5):679–90. doi: 10.1038/s41591-018-0016-8 - DOI - PMC - PubMed
    1. Runge HFP, Lacy S, Barrans S, Beer PA, Painter D, Smith A, et al.. Application of the LymphGen classification tool to 928 clinically and genetically-characterised cases of diffuse large B cell lymphoma (DLBCL). Br J Haematol. 2021;192(1):216–20. doi: 10.1111/bjh.17132 - DOI - PubMed
    1. Lacy SE, Barrans SL, Beer PA, Painter D, Smith AG, Roman E, et al.. Targeted sequencing in DLBCL, molecular subtypes, and outcomes: a Haematological Malignancy Research Network report. Blood. 2020;135(20):1759–71. doi: 10.1182/blood.2019003535 - DOI - PMC - PubMed